Wednesday, March 16, 2011

Is it necessary to add cholesterol to a liposome formulation?

The presence of cholesterol exerts a profound influence on the properties of the lipid bilayers of the liposomes. It has been known for several decades that the addition of cholesterol to a fluid phase bilayer (mainly unsaturated lipids) decreases its permeability to water. A liposome that is made from 100% unsaturated lipid in "fluid phase" can not hold its encapsulated content and the encapsulated water soluble drugs will leak out over time and therefore the addition of cholesterol is necessary in order to prevent the leakage of the encapsulated drug from the liposomes. Cholesterol molecules fill in the free space that was formed due to the kink in the chain of the unsaturated lipids and this will decrease the flexibility of the surrounding lipid chains. This interaction also increases the mechanical rigidity of fluid bilayers and decreases their lateral diffusion. In contrast, the addition of cholesterol to gel phase bilayers (mainly saturated lipids) disrupts local packing orders and increases the diffusion coefficient and decreases the elastic modulus. Liposomes made from 100% saturated lipids are leak-proof in the absence of the cholesterol. One of the main reasons for addition of cholesterol to liposomes that are made from saturated lipids is to decrease the phase transition temperature. The phase transition temperature of the mixture of the lipids in the liposomes will be decreased, but not eliminated, by the addition of cholesterol.

"Trigger release liposomes" such as temperature sensitive liposomes or radiation sensitive liposomes should be engineered in a way to have phase separated domains. The existence of the phase separated domains make the liposomes unstable upon trigger and therefore the liposomes release their content upon trigger.

Phase separation is necessary for engineering of the radiation sensitive liposomes because the polymerizable lipids should be adjacent to each other for the polymerization to happen. The addition of cholesterol molecules will disrupt the formation of the polymerizable domains because cholesterol molecules sit between the polymerizable molecules and prohibit the lipid molecules to exchange electrons and get polymerized upon radiation.

Temperature sensitive liposomes also demonstrate enhanced release of the encapsulated drug via grain boundary permeabilization when heated to their phase transition temperature. Addition of the cholesterol will also disrupt the formation of the grain boundary domains. Thermodox-a temperature sensitive liposomes at phase III- is a cholesterol free liposome.

Radiation sensitive liposomes and temperature sensitive liposomes are formulated by using saturated lipids. The addition of cholesterol to gel phase liposomes will increase the fluidity of the membrane and therefore all the gaps and imperfections that are formed in the lipid bilayers due to the trigger (radiation or heat) will be healed immediately and this will prevent the liposomes to leak more of their content upon trigger and this is undesirable. Trigger release liposomes should release as much of their content as possible upon trigger.

To see the original Q&A on Quora click here: